Pleiotropic effects for Parkin and LRRK2 in leprosy type-1 reactions and Parkinson's disease.

Emma J MacDougall, Erwin Schurr, Laurent Abel, Alexandre Alcaïs, Aurélie Cobat, Jean-François Trempe, Edward A Fon, Linda Adams, Ramanuj Lahiri, Geison Cambri, Vinicius M Fava, Mohamed A Eldeeb, Nathalie Croteau, Shao Tao, Vu Hong Thai, Marianna Orlova, Nguyen Van Thuc, Guillaume Lettre, Yong Zhong Xu

Journal: Proceedings of the National Academy of Sciences of the United States of America 2020;116(31):15616-15624

PMID: 31308240

Free Full Text on Atypon View on PubMed

Abstract

Type-1 reactions (T1R) are pathological inflammatory episodes and main contributors to nerve damage in leprosy. Here, we evaluate the genewise enrichment of rare protein-altering variants in 7 genes where common variants were previously associated with T1R. We selected 474 Vietnamese leprosy patients of which 237 were T1R-affected and 237 were T1R-free matched controls. Genewise enrichment of nonsynonymous variants was tested with both kernel-based (sequence kernel association test [SKAT]) and burden methods. Of the 7 genes tested 2 showed statistical evidence of association with T1R. For the gene an enrichment of nonsynonymous variants was observed in T1R-free controls ( = 1.6 × 10). This genewise association was driven almost entirely by the gain-of-function variant R1628P ( = 0.004; odds ratio = 0.29). The second genewise association was found for the Parkin coding gene (formerly ) where 7 rare variants were enriched in T1R-affected cases ( = 7.4 × 10). Mutations in both and are known causes of Parkinson's disease (PD). Hence, we evaluated to what extent such rare amino acid changes observed in T1R are shared with PD. We observed that amino acids in Parkin targeted by nonsynonymous T1R-risk mutations were also enriched for mutations implicated in PD ( = 1.5 × 10). Hence, neuroinflammation in PD and peripheral nerve damage due to inflammation in T1R share overlapping genetic control of pathogenicity.

Address: Program in Infectious Diseases and Immunity in Global Health, The Research Institute of the McGill University Health Centre, Montreal, QC, Canada H4A 3J1; [email protected] [email protected].; McGill International TB Centre, Montreal, QC, Canada H4A 3J1.; Program in Infectious Diseases and Immunity in Global Health, The Research Institute of the McGill University Health Centre, Montreal, QC, Canada H4A 3J1.; Montreal Heart Institute, Montreal, QC, Canada H1T 1C8.; Department of Medicine, Faculty of Medicine, Université de Montréal, Montréal, QC, Canada H3T 1J4.; Hospital for Dermato-Venereology, District 3, Ho Chi Minh City, Vietnam.; Division of Experimental Medicine, Faculty of Medicine, McGill University, Montreal, QC, Canada H3G 2M1.; The Translational Research in Respiratory Diseases Program, The Research Institute of the McGill University Health Centre, Montreal, QC, Canada H4A 3J1.; Centre for Structural Biology, Department of Pharmacology & Therapeutics, McGill University, Montreal, QC, Canada H3G 1Y6.; McGill Parkinson Program, Neurodegenerative Diseases Group, Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, QC, Canada H3A 2B4.; Graduate Program in Health Sciences, Pontifícia Universidade Católica do Paraná, Curitiba, PR, 80215-901, Brazil.; National Hansen's Disease Program, Health Resources and Services Administration, Baton Rouge, LA 70803.; Laboratory of Human Genetics of Infectious Diseases, Necker Branch, Institut National de la Santé et de la Recherche Médicale 1163, 75015 Paris, France.; Imagine Institute, Paris Descartes-Sorbonne Paris Cité University, 75015 Paris, France.; St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY 10065.; Department of Human Genetics, Faculty of Medicine, McGill University, Montreal, QC, Canada H3A 0C7.

DOI: 10.1073/pnas.1901805116

Link outs

Free resources

Full Text Sources:

Medical:

https://medlineplus.gov/mycobacterialinfections.ht...

Other Literature Sources:

https://www.lens.org/lens/search/patent/list?q=ref...

MeSH Terms: Female, Humans, Leprosy, Leucine-Rich Repeat Serine-Threonine Protein Kinase-2, Male, Mutation, Parkinson Disease, Ubiquitin-Protein Ligases